Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration.
BACKGROUND
In-stent restenosis, or renarrowing within a coronary stent, is the most ominous complication of percutaneous coronary intervention, caused by vascular smooth muscle cell (VSMC) migration into and proliferation in the intima. Although drug-eluting stents reduce restenosis, they delay the tissue healing of the injured arteries. No promising alternative anti-restenosis treatments are currently on the horizon.


METHODS
In endothelium-denudated mouse carotid arteries, oral morelloflavone-an active ingredient of the Thai medicinal plant Garcinia dulcis-significantly decreased the degree of neointimal hyperplasia, without affecting neointimal cell cycle progression or apoptosis as evaluated by Ki-67 and TUNEL staining, respectively. At the cellular level, morelloflavone robustly inhibited VSMC migration as shown by both scratch wound and invasion assays. In addition, morelloflavone prevented VSMCs from forming lamellipodia, a VSMC migration apparatus. Mechanistically, the inhibition by morelloflavone of VSMC migration was through its negative regulatory effects on several migration-related kinases, including FAK, Src, ERK, and RhoA. Consistently with the animal data, morelloflavone did not affect VSMC cell cycle progression or induce apoptosis.


RESULTS
These data suggest that morelloflavone blocks injury-induced neointimal hyperplasia via the inhibition of VSMC migration, without inducing apoptosis or cell cycle arrest.


CONCLUSIONS
We propose morelloflavone to be a viable oral agent for the prevention of restenosis, without compromising effects on the integrity and healing of the injured arteries.
Pinkaew
Decha
D
Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
Cho
Sung Gook
SG
Hui
David Y
DY
Wiktorowicz
John E
JE
Hutadilok-Towatana
Nongporn
N
Mahabusarakam
Wilawan
W
Tonganunt
Moltira
M
Stafford
Lewis J
LJ
Phongdara
Amornrat
A
Liu
Mingyao
M
Fujise
Ken
K
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D044946:Biflavonoids / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology / Q000517:prevention & control; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D029760:Garcinia / Q000737:chemistry*; D006965:Hyperplasia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D011554:Pseudopodia / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D001057:Apolipoproteins E; D044946:Biflavonoids; C105620:morelloflavone